Project Summary and Abstract: The United States currently faces an epidemic of diseases related to an inability to maintain a healthy body weight (weight homeostasis, WH). The influence of chronic stress on dysregulated WH is becoming increasingly appreciated. Dysregulated WH and chronic stress are correlated to both poorer quality of life and increased annual health care costs. Consequently, there is a need to understand the basis for which stress modulates WH. While both processes are controlled by the central nervous system (CNS), investigations are challenged by both the difficulty of modeling stress in a human-relevant context, and a heavy focus on the hypothalamic control of WH. Therefore, this proposal will focus on the interaction between the 1) CNS “signals” of stress, namely Corticotrophin Releasing Factor (CRF) and its receptors, and 2) Bed Nucleus of the Stria Terminalis (BNST), a structure both responsible for stress processing, and recently shown to control WH. Intriguingly, my preliminary loss-of-function studies have strongly suggested that neurons expressing CRF Receptor 1 (CRFR1) in the BNST (BNSTCRFR1) are necessary for maintenance of WH. The main objective of this proposal is to examine the role of BNSTCRFR1in the control of WH. My central hypothesis is that CRF input and signaling into BNSTCRFR1 is necessary to maintain WH via control of animal metabolism and behavior. Using viral, genetic, molecular and metabolic methodologies, I will test this hypothesis with three specific aims. In Aim 1, I will determine the peripheral mechanism of weight loss in BNSTCRFR1 loss of function. Then, in Aim 2, I will determine if CRF-specific signaling is the central mechanism by which BNSTCRFR1 control WH. Lastly, in Aim 3, I will explore BNSTCRFR1 inputs, especially those from CRF neurons. These studies are novel and innovative. They 1) elaborate on the circuitry, signaling, and functionality of a poorly characterized population within the BNST and 2) model stress using evolutionarily conserved peptides (e.g., CRF, CRFR1), facilitating the translation of findings into humans. Further, given the millions of Americans with both dysregulation of weight homeostasis and stress, these studies are significant. 1) elaborate on our mechanistic understanding of the neural basis of weight homeostasis control, and 2) provide avenues for the generation of novel therapeutics that may be helpful in curbing weight dysregulation and stress. These investigations will develop my skillset as an independent physician-scientist interested in studying the neural mechanisms of homeostatic control, using stress and WH as framework. With the mentorship of my sponsor and co-sponsor, Drs. Ben Arenkiel and Qingchun Tong, I will become exemplary in the use of mouse models, viruses, and imaging to interrogate the nervous system. Further, within the resource rich Baylor College of Medicine and Jan and Dan Duncan Neurologic Research Institute, I will have the ability to bu...